title: Use of an exposure-response model to aid early drug development of an oral sphingosine 1-phosphate receptor modulator.
abstract: Pharmacokinetic (PK) and exposure-response modeling of a selective sphingosine 1-phosphate receptor-1 modulator (CS-0777) was conducted in an iterative process to guide early clinical development decisions. A model based on preclinical data from monkeys was extrapolated to humans to support a single ascending dose (SAD) study. The model was updated after each cohort, providing guidance on both maximal inhibition and time to recovery for lymphocyte counts. A 2-compartment PK model with first-order absorption and elimination was found to describe the monkey and human datasets. The relationship between lymphocyte counts and active metabolite (M-1) concentrations was modeled via an indirect response model, whereby M-1 inhibited the reentry of lymphocytes to the circulation. The indirect-response model based on SAD data had an Imax of approximately 85% and an IC50 of 0.24 ng/mL. Additionally, based on SAD data, similar models were developed for lymphocyte subsets, including CD4 cells. Subsequently, simulations were utilized to design a multiple ascending dose study with adaptive dosing regimens that would meet targeted pharmacodynamic (PD) response thresholds (eg, minimum 40% reduction in lymphocytes) while maintaining CD4 counts above a reasonable safety threshold. In conclusion, model-based development and use of adaptive designs for dose optimization can reduce the time and number of subjects needed in early clinical development.
authors.affiliation: Daiichi Sankyo Pharma Development, 399 Thornall Street, Edison, NJ 08837, USA. srohatagi@dsus.com
authors.forename: Shashank
authors.initials: S
authors.lastname: Rohatagi
authors.forename: Hamim
authors.initials: H
authors.lastname: Zahir
authors.forename: James B
authors.initials: JB
authors.lastname: Moberly
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Truitt
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Inaba
authors.forename: Takaichi
authors.initials: T
authors.lastname: Shimozato
authors.forename: T J
authors.initials: TJ
authors.lastname: Carrothers
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000605:Amino Alcohols / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects*; D008246:Lysophospholipids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000502:physiology*; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000605:Amino Alcohols; C569297:CS 0777; D008246:Lysophospholipids; D011355:Prodrugs; D011758:Pyrroles; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D013110:Sphingosine